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Pyrazole derivative

a technology of pyrazole and derivatives, applied in the field of compounds, can solve problems such as movement deterioration, and achieve the effects of low metabolic stability, poor solubility, and us

Active Publication Date: 2015-03-17
MOCHIDA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a compound having a 4-heteroarylpyrazole-5-carboxylic acid amide structure and its pharmaceutical composition. This compound is a potent inhibitor of PDE10, an enzyme involved in the breakdown of cAMP in striatal GABA neurons. By inhibiting PDE10, the compound promotes the activation of the corpus striatum, which is involved in the pathophysiology of various diseases related to PDE10, such as mental disorders and neurodegenerative disorders. The pharmaceutical composition can be administered orally and is expected to be an effective treatment for these diseases. Additionally, the compounds of the present invention have good solubility, metabolic stability, and oral absorbability, and are only minimally impactful on the hERG channel.

Problems solved by technology

For example, deterioration of movements in Parkinson's disease is caused by excessive action of the indirect pathway, and excessive movements observed in disorders such as Huntington's disease are caused by excessive action of the direct pathway.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1.1

Synthesis of 1-methyl-4-(5-methylpyridin-2-yl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Synthesis of methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

[0683]A 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.37 g) and potassium acetate (3.5 g) were added to a dimethyl sulfoxide (10 ml) solution of 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (2.0 g) and 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (4.1 g). The obtained mixture was stirred in a nitrogen atmosphere at 100° C. for 4 hours. Thereafter, the reaction solution was cooled, and water (50 ml) was then added thereto, followed by extraction with ethyl acetate (100 ml) twice. Organic layers were gathered. The gathered organic layer was successively washed with water and a saturated saline, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then puri...

example 1.2

Synthesis of 1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Synthesis of methyl 1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylate

[0687]Using 2-bromo-4-methylthiazole (106 mg), the title compound (110 mg) was obtained in a white amorphous form by the same method as that of (Example 1.1) or a method equivalent thereto.

Synthesis of 1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylic acid

[0688]Using the methyl 1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylate (100 mg) obtained in (Example 1.2) , the title compound (58 mg) was obtained in the form of a beige solid by the same method as that of (Example 1.1) or a method equivalent thereto.

Synthesis of 1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

[0689]Using the 1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylic acid (27 mg) obtained in (Example 1.2) , the title compound (6.0 mg) was obtained in th...

example 1.3

Synthesis of 4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Synthesis of methyl 4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

[0690]Using 2-bromo-4-(difluoromethyl)thiazole (600 mg), the title compound (590 mg) was obtained in a light brown amorphous form by the same method as that of (Example 1.1) or a method equivalent thereto.

Synthesis of 4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

[0691]An aqueous solution (0.28 ml) of 1 N sodium hydroxide was added to a methanol (1.4 ml) solution of the methyl 4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (30 mg) obtained in (Example 1.3) . The obtained mixture was stirred at 60° C. for 30 minutes. Thereafter, the solvent was distilled away under reduced pressure, and the obtained residue was then subjected to azeotropy with toluene (10 ml). Subsequently, diisopropylethyla...

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Abstract

It has been desired to develop a pharmaceutical composition, which is used in agents for preventing and / or treating various diseases related to PDE10 (e.g. mental disorder and neurodegenerative disorder). The present invention provides: compounds having PDE10 inhibitory effect, in particular, compounds having a 4-heteroarylpyrazole-5-carboxylic acid amide structure represented by the following formula (I), or their pharmaceutically acceptable salts, or their solvates; pharmaceutical compositions comprising, as active ingredients, the compounds, or their pharmaceutically acceptable salts, or their solvates; and medical use of the compounds, or their pharmaceutically acceptable salts, or their solvates.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation of PCT International Application No. PCT / JP2014 / 054773, filed on Feb. 26, 2014, which claims priority under 35 U.S.C. 119(a) to Patent Application No. 2013-038030, filed in Japan on Feb. 27, 2013, all of which are hereby expressly incorporated by reference into the present application.TECHNICAL FIELD[0002]The present invention relates to a compound having phosphodiesterase 10 (hereinafter referred to as “PDE10”) inhibitory effect, in particular, a compound having a 4-heteroarylpyrazole-5-carboxylic acid amide structure represented by the following formula (I), or a pharmaceutically acceptable thereof, or a solvate thereof; and a pharmaceutical composition comprising, as an active ingredient, the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an agent for preventing and / or treating various diseases related to PDE10 (e.g. mental disorders and neurodegenerative disorders)....

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D498/02A61K31/535C07D471/04
CPCC07D471/04C07D401/04C07D403/04C07D417/04A61P25/00A61P25/08A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32A61P25/36A61P3/04A61P43/00A61K31/437A61K31/444A61K31/497A61K31/506A61K31/5377A61K31/501A61K45/06
Inventor OKANO, AKIHIROMAKABE, MUNEYOSHI
Owner MOCHIDA PHARM CO LTD
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